The prior art on the synthesis of bis[3-(N,N-dialkylamino)propyl]ethers is much less abundant than on the synthesis of bis[3-(N,N-dialkylamino)ethyl]ethers. The synthesis of the latter is mainly based on the chemistry of ethylene oxide, which is the precursor of the ethoxyethyl pattern connecting the two amine functions.
The propoxypropyl pattern that connects the two amine functions of bis[3-(N,N-dialkylamino)ethyl]ethers cannot be based on the chemistry of propylene oxide that would lead to bis[2-(N,N-dialkylamino)propyl]ethers and not bis[3-(N,N-dialkylamino)propyl]ethers as desired. In fact, few studies on the synthesis of bis[3-(N,N-dialkylamino) propyl]ethers are available.
The synthesis of bis[3-(N,N-dialkylamino)propyl]ethers is described by J. Fakstorp et al. The synthesis of bis[3-(N,N-dimethylamino)propyl]ether is described in Acta. Chem. Scand., 11 (1957), 1698-1705, by reaction of 3-(dimethylamino)-propanol with 1-chloro-3-(dimethylamino)-propane. This reaction results from the condensation of the alkaline alcoholate, sodium alcoholate for example, of the previously prepared 3-(dimethylamino)-propanol on 1-chloro-3-(dimethylamino)-propane. By doing so, for each mole of bis[3-(N,N-dimethylamino)propyl]ether formed, one mole of alkaline chloride, sodium chloride for example, is produced.
The same author describes in Acta. Chem. Scand., 8 (1954), 350-353, the synthesis of bis[3-(N,N-diethylamino)propyl]ether by reaction of 3-(diethylamino)-propanol with 1-chloro-3-(diethylamino)-propane under similar conditions.
U.S. Pat. No. 3,480,675 (1969) claims an improvement of this operating mode by conducting a single stage in the presence of a base allowing in-situ generation of 3-(dialkylamino)-propanol alcoholate. Here also, one mole of alkaline chloride, sodium chloride for example, is produced per mole of bis[3-(N,N-dialkylamino)propyl]ether.
These synthesis routes use 1-chloro-3-(dimethylamino)-propane or 1-chloro-3-(diethylamino)-propane as the reagent. These molecules result from the chlorination of 3-(dimethylamino)-propanol or 3-(diethylamino)-propanol. This reaction is carried out using a chlorinating agent that can be, for example, hydrochloric acid, thionyl chloride, phosphorus trichloride or phosphorus pentachloride. These chlorinating agents are corrosive and sometimes generate by-products such as sulfur dioxide in the case of thionyl chloride. Their large-scale industrial use is therefore not desirable.
U.S. Pat. No. 4,247,482 (1981) provides a synthesis route where the 3-(dialkylamino)-propanol is first converted to sodium alcoholate by reaction with a base, then converted by reaction with sulfur trioxide to an intermediate product 3-(dialkylamino)-propane-1-sodium sulfate, which by condensation with the sodium alcoholate of 3-(dialkylamino)-propanol leads to bis[3-(N,N-dialkylamino)propyl]ether by generating an equimolar proportion of sodium sulfate.
Salt formation is inevitable in view of the synthesis routes described by the prior art. In all the cases described, one mole of salt per mole of bis[3-(N,N-dialkylamino)propyl]ether is inevitably formed. The generation of salts in large amounts, which have to be removed later or which are difficult to manage, has become incompatible with the development of modern industrial chemical processes. Thus, the technologies described in the prior art are today hardly compatible with the large-scale industrial production of bis[3-(N,N-dialkylamino)propyl]ether.